Frontotemporal network connectivity during memory encoding is increased with aging and disrupted by beta-amyloid

Abstract

Approximately 30% of cognitively normal older adults harbor brain β-amyloid (Aβ), a prominent feature of Alzheimer's disease associated with neural alterations and episodic memory decline. We examined how aging and Aβ deposition affect neural function during memory encoding of visual scenes using functional magnetic resonance imaging (fMRI) in humans. Thirty-six cognitively normal older people underwent fMRI scanning, and positron emission tomography with [(11)C] Pittsburgh compound B to measure fibrillar brain Aβ; 15 young subjects were studied with fMRI. Older adults without Aβ deposition showed reduced regional brain activation (compared with young subjects) with decreased task-independent functional connectivity between parahippocampal gyrus and prefrontal cortex. In this network, task-related connectivity was increased compared with young subjects, and the degree of connectivity was related to memory performance. In contrast, older individuals with Aβ deposition showed no such increased task-related network connectivity, but did display increased regional activity unassociated with performance. These findings suggest that network connectivity plays a significant role in compensating for reduced regional activity during successful memory encoding in aging without Aβ deposition, while in those with Aβ this network compensation fails and is accompanied by inefficient regional hyperactivation.

Figure 1.

Brain activity for successfully encoded (HC-HIT) versus forgotten items (MISS) in young (a), PIB− OLD (b), and PIB+ OLD (c) groups. Suprathreshold regions are overlaid on the inflated cortical surface in MNI space. The color scale represents t values with warm colors indicating significantly increased activity for successfully encoded items compared with forgotten items (HC-HIT > MISS) and cool colors indicating an opposite pattern (MISS > HC-HIT) in each group. Maps show suprathreshold regions significant at p < 0.05 voxel level, with FDR correction at p < 0.05 at cluster level for multiple comparisons across the whole-brain volume. L, left hemisphere; R, right hemisphere.

Figure 2.

Effects of age and Aβ deposition on brain activity for successfully encoded (HC-HIT) versus forgotten items (MISS). a, Age-related differences in brain activity for successfully encoded versus forgotten items. Suprathreshold regions are overlaid on the inflated cortical surface in MNI space. The color scale represents t values with warm colors indicating significantly increased activity in young subjects compared with PIB−OLD for successfully encoded items compared with forgotten items. b, Aβ deposition shows greater brain activity for HC-HIT than MISS conditions. Suprathreshold regions are overlaid on the inflated cortical surface in MNI space. The color scale represents t values with warm colors indicating significantly increased activity in PIB+ OLD compared with PIB− OLD for successfully encoded items compared with forgotten items. No region shows significantly increased activity in PIB− OLD compared with PIB+ OLD adults in the same contrast. Maps show suprathreshold regions significant at p < 0.05 voxel level, with FDR correction at p < 0.05 at cluster level for multiple comparisons across the whole-brain volume. L, left hemisphere; R, right hemisphere.

Figure 3.

Effects of age and Aβ deposition on PPI connectivity representing stronger coupling for successfully encoded than forgotten items. a, Stronger connectivity between rPHG and PFC in PIB− OLD than YOUNG during successful memory encoding (HC-HIT vs MISS conditions). Suprathreshold regions are overlaid on the inflated cortical surface in MNI space. The color scale represents t values with warm colors indicating significantly stronger connectivity between rPHG and medial and lateral PFC in PIB− OLD compared with YOUNG. No region shows significantly stronger connectivity with the rPHG seed region in YOUNG compared with PIB− OLD adults. b, Stronger connectivity between rPHG and PFC and VA in PIB− OLD than PIB+ OLD during successful memory encoding (HC-HIT vs MISS conditions). Suprathreshold regions are overlaid on the inflated cortical surface in MNI space. The color scale represents t values with warm colors indicating significantly stronger connectivity between the rPHG and other voxels. No region shows significantly stronger connectivity with the rPHG seed region in PIB+ OLD compared with PIB− OLD adults. Maps show suprathreshold regions significant at p < 0.05 voxel level, with FDR correction at p < 0.05 at cluster level for multiple comparisons across the whole-brain volume. L, left hemisphere; R, right hemisphere.

Figure 4.

Association between recognition accuracy and differential brain activity for PIB− OLD and PIB+ OLD. a, In PIB− OLD, better recognition accuracy was related to stronger PPI connectivity between regions that showed an age-related increase in PPI connectivity as depicted in Figure 3a. A scatterplot illustrates the positive relationship between recognition accuracy and averaged parameter estimates of clusters showing significantly stronger PPI connectivity in PIB− OLD than young subjects during successful memory encoding. The relationship between recognition accuracy and parameter estimates was statistically significant, β = 0.44, p < 0.05, controlling for age and sex. b, The regressions between regional brain activity showing age-related decreases, as depicted in Figure 2a, and recognition accuracy, however, were not significant (β = −0.05, p > 0.5), controlling for age and sex. c, d, In PIB+ OLD, recognition accuracy was not related to either PPI connectivity in brain regions showing Aβ-related reduction as illustrated in Figure 3b (β = −0.30, p > 0.4) or brain activity in regions showing an Aβ-related increase in regional activity, as illustrated in Figure 2b (β = 0.15, p > 0.5), controlling for age and sex.

Figure 5.

Stronger task-independent functional connectivity between rPHG and other brain regions in YOUNG than PIB− OLD. Suprathreshold regions are overlaid on the inflated cortical surface in MNI space. The color scale represents t values with warm colors indicating significantly stronger task-independent functional connectivity between rPHG and lateral PFC, anterior cingulate, lateral parietal cortices, and precuneus in YOUNG compared with PIB− OLD. No region shows significantly stronger connectivity with the rPHG seed region in PIB− OLD adults compared with YOUNG. Maps show only suprathreshold regions significant at p < 0.005 voxel level, with FDR correction at p < 0.05 at cluster level. L, left hemisphere; R, right hemisphere.

Figure 6.

The interaction effect between ApoE genotypes and Aβ deposition on PPI connectivity and regional brain activity for successfully encoded versus forgotten items. a, Brain regions showing the interaction effect (interaction between PIB group membership and ApoE4 status) on PPI connectivity are depicted in cool colors and brain regions showing the effect of Aβ deposition (PIB+ OLD < PIB− OLD) on PPI connectivity, as identified in Figure 3b, are depicted in warm colors. b, Brain regions showing the interaction effect (interaction between PIB group membership and ApoE4 status) on regional brain activity for successful encoding are depicted in cool colors, and brain regions showing the effect of Aβ deposition (PIB+ OLD > PIB− OLD) on regional brain activity for successful encoding, as identified in Figure 2b, are depicted in warm colors. c, Left, A two-way ANOVA demonstrates the interaction effect shown in a (i.e., brain regions depicted in cool colors). Right, A two-way ANOVA shows only a main effect of PIB group on PPI connectivity measures extracted from brain regions showing the effect of Aβ deposition in the whole-brain analysis (i.e., brain regions depicted in warm colors in a). d, Left, A two-way ANOVA demonstrates the interaction effect shown in b (i.e., brain regions depicted in cool colors). Right, A two-way ANOVA shows only a main effect of PIB group on parameter estimates extracted from brain regions showing the effect of Aβ deposition on regional activity in the whole-brain analysis (i.e., brain regions depicted in warm colors in b). Maps show suprathreshold regions significant at p < 0.05 voxel level, with corrected p < 0.05 at cluster level for multiple comparisons across the whole-brain volume. Suprathreshold voxels were superimposed on axial slices. Age was controlled in all ANOVAs. L, left hemisphere; R, right hemisphere.

Figure 7.

Relationships between age, Aβ deposition, brain function, and cognition. Each brain image represents the projection of data from Figures 2, 3, and 5 onto the inflated cortical surface of the right hemisphere along with brain function and behavior relationships as shown in Figure 4a, and d. The present findings suggest differential age and Aβ-related changes in regional activity and MTL-seeded connectivity during episodic encoding. Age (in the absence of Aβ) is associated with failure to engage brain regions crucial to encoding new information, such as MTL structures, and also with reduced task-independent connectivity across brain regions. These changes are accompanied by increased task-dependent functional connectivity contributing to preserved EM performance in older adults. Elevated Aβ deposition, on the other hand, recruits more local activity in conjunction with the failure to engage task-dependent functional coupling to perform EM encoding equivalently to older adults without Aβ deposition. This increased regional activity is not associated with memory function. Increased regional activity and task-independent connectivity for YOUNG compared with PIB− OLD are shown in green and blue, respectively, while the overlapping regions are shown in cyan; increased task-dependent connectivity for PIB− OLD compared with either YOUNG or PIB+ OLD are shown in yellow; increased regional activity for PIB+ OLD compared with PIB− OLD is shown in orange/red.